The invention relates to novel pyrrolopyridinone derivatives, intermediates used in, synthesis of and pharmaceutical compositions containing the compounds and their use for the treatment of sexual dysfunction. The compounds of the present invention are phosphodiesterase inhibitors useful for the treatment of sexual dysfunction, more particularly male erectile dysfunction.
Erectile dysfunction (ED) is defined as the inability to achieve or maintain an erection sufficiently rigid for satisfactory sexual intercourse. Currently it is estimated that approximately 7-8% of the male population suffer from some degree of ED, the equivalent of at least 20 million men in the United States alone. Since the likelihood of ED increases with age, it is projected that the incidence of this condition will rise in the future as the average age of the population increases.
Male erectile dysfunction may be the consequence of psychogenic and/or organic factors. Although ED is multi-factorial, certain sub-groups within the male population are more likely to present with the symptoms of the disorder. In particular, patients with diabetes, hypertension, heart disease, and multiple sclerosis have a particularly high prevalence of ED. In addition, patients who take certain classes of drugs such as antihypertensives, antidepressants, sedatives, and anxiolytics are more prone to suffer from ED.
Treatments for ED include a variety of pharmacologic agents, vacuum devices, and penile prostheses. Among the pharmacologic agents, papaverine, phentolamine, and alprostadil are currently used in practice. These agents are only effective after direct intracavernosal or intraurethral injection, and are associated with side effects such as priapism, fibrosis, penile pain and hematoma at the injection site. Vacuum devices are a noninasive alternative treatment for ED. These devices produce an erection by creating a negative pressure around the shaft of the penis resulting in an increased blood flow into the corpus cavernosum via passive arterial dilation. Although this form of therapy is frequently successful in ED of organic origin, complaints include the lack of spontaneity and the time involved in using a mechanical device, and difficulty and discomfort with ejaculation. A variety of semi-rigid or inflatable penile prostheses have been used with some success, particularly in diabetic men. These devices are generally considered when other treatment options have failed, and are associated with an increased risk of infection and ischemia.
Recently, the phosphodiesterase V (PDEV) inhibitor, sildenafil (Viagra(copyright)) was approved by the FDA as an orally effective medication for the treatment of ED. Sildenafil, 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)phenyl]-1-methyl-3n-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7-one and a number of related analogs and their use as antianginal agents are described in U.S. Pat. Nos. 5,250,534 and 5,346,901. The use of sildenafil and related analogs for treating male erectile dysfunction is described in PCT International Application Publication No. WO 94/28902, published Dec. 22, 1994. In clinical studies, the drug improved sexual function in about 70% of the men who suffer from ED of psychogenic or organic etiology. However, the drug showed less dramatic efficacy in patients who had undergone a radical prostatectomy, with improved erections in 43% of patients who took sildenafil versus 15% on placebo. In addition, the use of sildenafil is associated with several undesirable side effects including headache, flushing and disrupted color vision which result from non-selective effects on a variety of tissues. In spite of these shortcomings, the drug is viewed by patients as preferable to other treatments which involve the introduction of medication directly into the penis via injection, the use of an external device or a surgical procedure.
Daugan et. al, in U.S. Pat. No. 5,859,009 and EP 0740668 B1 describe the synthesis of a series of tetracyclic derivatives as inhibitors of cyclic guanosine 3xe2x80x2,5xe2x80x2 monophosphate specifically phosphodiesterase, and their use in treating cardiovascular disorders. Daugan et. al., in WO97/03675 teach the use of the tetracyclic derivatives for the treatment of impotence.
Garinaux, J.-F. et al., in Tetrahedron Letters 38(17), (1997), pp 2997-3000 disclose the synthesis of tricyclic quinolone derivatives via oxidation of 1,2,3,4-tetrahydro-xcex2-carbolines.
Pfenninger, E. in DE 2803541 and U.S. Pat. No. 4,235,907 discloses substituted 9H-pyrrolo-[3,4-b]quinolin-9-ones and their use in the treatment of allergic asthma.
Sexually stimulated penile erection results from a complex interplay of physiological processes involving the central nervous system, the peripheral nervous system, and the smooth muscle. Specifically, release of nitric oxide from the non-adrenergic, non-cholinergic nerves and endothelium activates guanylyl cyclase and increases intracellular cGMP levels within the corpus cavernosum. The increase in intracellular cGMP reduces intracellular calcium levels, resulting in trabecular smooth muscle relaxation, which, in turn, results in corporal volume expansion and compression of the sub-tunical venules leading to penile erection.
PDEV has been found in human platelets and vascular smooth muscle, suggesting a role for this enzyme in the regulation of intracellular concentrations of cGMP in cardiovascular tissue. In fact, inhibitors of PDEV have been shown to produce endothelial-dependent vasorelaxation by potentiating the increases in intracellular cGMP induced by nitric oxide. Moreover, PDEV inhibitors selectively lower the pulmonary arterial pressure in animal models of congestive heart failure and pulmonary hypertension. Hence in addition to their utility in ED, PDEV inhibitors would likely be of therapeutic benefit in conditions like heart failure, pulmonary hypertension, and angina.
Agents that increase the concentration of cGMP in penile tissue, either through enhanced release or reduced breakdown of cGMP, are expected to be effective treatments for ED. The intracellular levels of cGMP are regulated by the enzymes involved in its formation and degradation, namely the guanylate cyclases and the cyclic nucleotide phosphodiesterases (PDEs). To date, at least nine families of mammalian PDEs have been described, five of which are capable of hydrolyzing the active, cGMP, to the inactive, GMP, under physiological conditions (PDEs I, II, V, VI, and IX). PDE V is the predominant isoform in human corpus cavernosum. Inhibitors of PDEV, therefore, would be expected to increase the concentration of cGMP in the corpus cavernosum and enhance the duration and frequency of penile erection.
Additionally, selective PDE inhibitors are known to be useful in the treatment of various disorders and conditions including male erectile dysfunction (ED), female sexual arousal dysfunction, female sexual dysfunction related to blood flow and nitric oxide production in the tissues of the vagina and clitoris, premature labor, dysmenorrhea, cardiovascular disorders, atherosclerosis, arterial occlusive disorders, thrombosis, coronary rest stenosis, angina pectoris, myocardial infarction, heart failure, ischemic heart disorders, hypertension, pulmonary hypertension, asthma, intermittent claudication and diabetic complications.
Accordingly, it is an object of the invention to identify compounds which increase the concentration of cGMP in penile tissue through the inhibition of phosphodiesterases, specifically PDEV. It is another object of the invention to identify compounds which are useful for the treatment of sexual dysfunction, particularly erectile dysfunction and/or impotence in male animals and sexual dysfunction in female animals. Still another object of the invention is to identify methods for treating sexual dysfunction, especially erectile dysfunction, using the compounds of the present invention.
It is another object of the invention to identify compounds which are useful for the treatment of conditions of disorders mediated by PDEV, such as male erectile dysfunction, female sexual dysfunction, cardiovascular disorders, atherosclerosis, arterial occlusive disorders, thrombosis, coronary reststenosis, angina pectoris, myocardial infarction, heart failure, ischemic heart disorders, hypertension, pulmonary hypertension, asthma, intermittent claudication or diabetic complications.
We now describe a series of pyrrolopyridinone derivatives with the ability to inhibit phosphodiesterase type V in enzyme assays.
The present invention provides novel pyrrolopyridinone derivative compounds useful as phosphodiesterase inhibitors. More particularly, the present invention is directed to compounds of the general formula (I) or (II): 
wherein
R1 is selected from the group consisting of hydrogen, carboxy, xe2x80x94C(O)xe2x80x94C1-C6alkyl, xe2x80x94C(O)xe2x80x94C1-C6alkoxy, xe2x80x94C(O)xe2x80x94NHxe2x80x94C1-C6alkyl-NH2, xe2x80x94C(O)xe2x80x94NHxe2x80x94C1-C6alkyl-NHRA, xe2x80x94C(O)xe2x80x94NHxe2x80x94C1-C6alkyl-N(RA)2, xe2x80x94C(O)xe2x80x94NH2, xe2x80x94C(O)xe2x80x94NHRA, xe2x80x94C(O)xe2x80x94N(RA)2, xe2x80x94C1-C6alkyl-NH2, xe2x80x94C1-C6alkyl-NHRA, xe2x80x94C1-C6alkyl-N(RA)2, xe2x80x94NHxe2x80x94C1-C6alkyl-N(RA)2;
where each RA is independently selected from the group consisting of C1-C6alkyl, aryl, C1-C6aralkyl and heteroaryl, where the aryl, aralkyl or heteroaryl may be optionally substituted with one to three RB;
where each RB is independently selected from the group consisting of halogen, nitro, cyano, C1-C6alkyl, C1-C6alkoxy, C1-C6alkylcarbonyl, carboxyC1-C6alkyl, C1-C6alkylsulfonyl, trifluoromethyl, amino, di(C1-C6alkyl)amino, acetylamino, carboxyC1-C6alkylcarbonylamino, hydroxyC1-C6alkylamino, NHRA and N(RA)2;
R2 is selected from the group consisting of C5-C10alkyl (optionally substituted with one to three substituents independently selected from halogen, hydroxy, nitro, amino, NHRA or N(RA)2), aryl (optionally substituted with one to three substituents independently selected from RC), cycloalkyl (optionally substituted with one to three substituents independently selected from RA), heteroaryl (optionally substituted with one to three substituents independently selected from RC), and heterocycloalkyl (optionally substituted with one to three substituents independently selected from RC);
where RC is selected from the group consisting of halogen, nitro, cyano, C1-C6alkyl, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, NH2, NH(C1-C6alkyl) and N(C1-C6alkyl)2;
R3 is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6alkylcarbonyl, C2-C6alkenylcarbonyl and C2-C6alkynylcarbonyl;
b is an integer from 0 to 4;
R4 is independently selected from the group consisting of halogen, hydroxy, carboxy, oxo, nitro, C1-C6alkyl, C1-C6alkoxy, C1-C6alkoxycarbonyl, trifluoromethyl, phenyl (wherein the phenyl group may be optionally substituted with one to three substituents independently selected from RD), phenylsulfonyl, naphthyl, C1-C6aralkyl, xe2x80x94O-aralkyl, (wherein the aralkyl group may be optionally substituted with one to three substituents independently selected from RD), heteroaryl (wherein the heteroaryl may be optionally substituted with one to three substituents independently selected from RD), heterocycloalkyl, NH2, 
where each RD is independently selected from halogen, hydroxy, carboxy, oxo, C1-C4alkyl, C1-4alkylthio, hydroxyC1-4alkyl, C1-C4alkoxy, C1-C4alkyoxycarbonyl, C1-C4alkylcarbonyl, trifluoromethyl, trifluoromethoxy, NH2, NHRA, N(RA)2, C(O)N(RA)2, acetylamino, nitro, cyano, formyl, C1-C6alkylsulfonyl, carboxyC1-C6alkyl and aralkyl;
c is an integer from 0 to 4;
R5 is independently selected from the group consisting of halogen, nitro, hydroxy, C1-C6alkyl, C1-C6alkoxy, xe2x80x94NH2, xe2x80x94NHRA, xe2x80x94N(RA)2, xe2x80x94ORA, xe2x80x94C(O)NH2, xe2x80x94C(O)NHRA, xe2x80x94C(O)N(RA)2, xe2x80x94NHC(O)RA, xe2x80x94SO2NHRA, xe2x80x94SO2N(RA)2, where RA is as defined above, phenyl (optionally substituted with one to three substituents independently selected from RB), heteroaryl (optionally substituted with one to three substituents independently selected from RB) and heterocycloalkyl (optionally substituted with one to three substituents independently selected from RB);
a is an integer from 0 to 1;
Y selected from the group consisting of xe2x80x94C1-C6alkyl-, xe2x80x94C(O)xe2x80x94, xe2x80x94(C1-C6alkyl)carbonyl-, xe2x80x94(C2-C6alkenyl)carbonyl-, xe2x80x94(C2-C6alkynyl)carbonyl-, -carbonyl(C1-C6alkyl)-, -carbonyl(C2-C6alkenyl)-, xe2x80x94C(O)Oxe2x80x94(C1-C6alkyl)-, xe2x80x94C(S)xe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94(C1-C6alkyl)sulfonyl-, -sulfonyl(C1-C6alkyl)-, xe2x80x94C(O)NHxe2x80x94, xe2x80x94C(O)NHxe2x80x94(C1-C6alkyl)-, xe2x80x94C(O)(C3-C7cycloalkyl)- and xe2x80x94(C3-C7cycloalkyl)-C(O)xe2x80x94; 
is selected from the group consisting phenyl, furyl, thienyl and pyrrolyl; 
is selected from the group consisting of aryl, heteroaryl, cycloalkyl and heterocycloalkyl;
provided that when R1 is hydrogen, R3 is hydrogen, b is 0, c is 0, a is 1, Y is xe2x80x94CH2xe2x80x94, 
is phenyl and 
is phenyl, then R2 is not trimethoxyphenyl, (i.e. the compound is not 1,2,3,4-tetrahydro-2-(phenylmethyl)-3-(3,4,5-trimethoxyphenyl)-9H-pyrrolo[3,4-b]quinolin-9-one);
and pharmaceutically acceptable salts thereof.
Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the compounds described above. An illustration of the invention is a pharmaceutical composition made by mixing any of the compounds described above and a pharmaceutically acceptable carrier. Illustrating the invention is a process for making a pharmaceutical composition comprising mixing any of the compounds described above and a pharmaceutically acceptable carrier.
Exemplifying the invention is a method of treating a condition selected from the group consisting of male erectile dysfunction (ED), impotence, female sexual dysfunction, female sexual arousal dysfunction, female sexual dysfunction related to blood flow and nitric oxide production in the tissues of the vagina and clitoris, premature labor, dysmenorrhea, cardiovascular disorders, atherosclerosis, arterial occlusive disorders, thrombosis, coronary rest stenosis, angina pectoris, myocardial infarction, heart failure, ischemic heart disorders, hypertension, pulmonary hypertension, asthma, intermittent claudication and diabetic complications in a subject in need thereof comprising administering to the subject a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.
An example of the invention is a method for increasing the concentration of cGMP in penile tissue through the inhibition of phosphodiesterases, specifically PDEV, in a male subject in need thereof comprising administering to the subject an effective amount of any of the compounds or pharmaceutical compositions described above.
Further exemplifying the invention is a method of producing endothelial-dependent vasorelaxation by potentiating the increases in intracellular cGMP induced by nitric oxide in a subject in need thereof comprising administering to the subject an effective amount of any of the compounds or pharmaceutical compositions described above.
An example of the invention is the use of any of the compounds described above in the preparation of a medicament for: (a) treating sexual dysfunction, especially male erectile dysfunction, (b) treating impotence, (c) increasing the concentration of cGMP in penile tissue through inhibition of phosphodiesterase, especially PDEV and/or (d) treating a condition selected from the group consisting of premature labor, dysmenorrhea, cardiovascular disorders, atherosclerosis, arterial occlusive disorders, thrombosis, coronary reststenosis, angina pectoris, myocardial infarction, heart failure, ischemic heart disorders, hypertension, pulmonary hypertension, asthma, intermittent claudication and diabetic complications in a subject in need thereof.